dbSNP rs117423374: IL10RA:p.Arg412Gln (chr11-117999139-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001558.4(IL10RA):c.1235G>A(p.Arg412Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000977 in 1,613,682 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R412W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 3 hom. )

Consequence

IL10RA
NM_001558.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: -0.0800

Publications

5 publications found

Variant links:

Genes affected

IL10RA (HGNC:5964): (interleukin 10 receptor subunit alpha) The protein encoded by this gene is a receptor for interleukin 10. This protein is structurally related to interferon receptors. It has been shown to mediate the immunosuppressive signal of interleukin 10, and thus inhibits the synthesis of proinflammatory cytokines. This receptor is reported to promote survival of progenitor myeloid cells through the insulin receptor substrate-2/PI 3-kinase/AKT pathway. Activation of this receptor leads to tyrosine phosphorylation of JAK1 and TYK2 kinases. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Jan 2009]

IL10RA Gene-Disease associations (from GenCC):

inflammatory bowel disease 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
IL10-related early-onset inflammatory bowel disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IL10RA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057965517).

BP6

Variant 11-117999139-G-A is Benign according to our data. Variant chr11-117999139-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 538054.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000643 (98/152340) while in subpopulation NFE AF = 0.00119 (81/68024). AF 95% confidence interval is 0.000981. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001558.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL10RA	NM_001558.4	MANE Select	c.1235G>A	p.Arg412Gln	missense	Exon 7 of 7	NP_001549.2
IL10RA	NM_001440423.1		c.788G>A	p.Arg263Gln	missense	Exon 5 of 5	NP_001427352.1
IL10RA	NR_026691.2		n.1439G>A		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL10RA	ENST00000227752.8	TSL:1 MANE Select	c.1235G>A	p.Arg412Gln	missense	Exon 7 of 7	ENSP00000227752.4
IL10RA	ENST00000529924.6	TSL:1	n.2813G>A		non_coding_transcript_exon	Exon 6 of 6
IL10RA	ENST00000951964.1		c.1229G>A	p.Arg410Gln	missense	Exon 7 of 7	ENSP00000622023.1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000486

AC:

122

AN:

250930

AF XY:

0.000472

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00101

AC:

1479

AN:

1461342

Hom.:

Cov.:

AF XY:

0.000975

AC XY:

709

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00128

AC:

1423

AN:

1111548

Other (OTH)

AF:

0.000745

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

183

275

366

458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000643

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000985

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inflammatory bowel disease 28 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.4

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.076

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.59

M_CAP

Benign

0.0026

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

-0.080

PrimateAI

Benign

0.20

PROVEAN

Benign

1.3

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.022

MVP

0.28

MPC

0.24

ClinPred

0.039

GERP RS

-2.7

Varity_R

0.020

gMVP

0.048

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over